Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disease of global prevalence. The long term use of conventional anti-inflammatory drugs for the treatment of RA is associated with severe adverse reactions. This has led to an exponential increase in the use of natural products, including traditional Chinese medicine (TCM), in the U.S. and other countries. However, despite the extensive utilization of complementary and alternative medicine (CAM) products over decades/centuries globally, the underlying mechanisms of action of many of them are poorly defined, if at all. This limitation is one of the reasons for skepticism among medical professionals and the public about the use of herbal products. Celastrus is a Chinese herbal medicine that has long been used to treat a variety of inflammatory diseases, including RA. In our preliminary studies in adjuvant- induced arthritis (AA), a rat model of human RA, we observed that feeding Celastrus to Lewis rats affords significant protection against inflammatory arthritis. Furthermore, the pro-inflammatory cytokines interleukin-17 (IL-17) and IL-6 were suppressed in Celastrus-treated rats versus control rats, altering the antigen-induced cytokine balance in favor of disease attenuation. We hypothesize that this Celastrus-induced reduction of IL- 17 response is owing to an altered balance between CD4+ T helper 17 (Th17) and CD4+CD25+Foxp3+ T regulatory cells (Treg), which is influenced in part by altered processing and presentation of the disease- related antigen, mycobacterial heat-shock protein 65 (Bhsp65). We further suggest that Celastrus might have additive or synergistic effect when combined with an immunotherapeutic agent that by itself inhibits arthritis via reduction of IL-17. In this study, we plan to - (Aim 1) determine the relative frequency of Th17 and Treg in Celastrus-treated versus control rats during the course of AA; (Aim 2) examine the influence of Celastrus treatment of rats on the epitope-specific T cell response against Bhsp65; and (Aim 3) test whether Celastrus has an additive/synergistic anti-arthritic effect when used in combination with a disease-modulating peptide of rat heat-shock protein (R465) or the conventionally used anti-arthritic drug, methotrexate. The results of this study would help significantly in establishing a reliable scientific basis for the use of Celastrusin RA, in translational research on the use of TCM herbs in RA, and in developing better CAM-based therapeutic approaches for RA. [In the process of working on this herbal CAM-centered project, and by actively interacting with and participating in activities organized by the Center o Integrative Medicine (CIM) at my institution, I hope to gain high level of training and experience in CAM.] PUBLIC HEALTH RELEVANCE: Traditional Chinese medicine (TCM) and other natural plant products are increasingly being used by patients with rheumatoid arthritis (RA), but the mechanisms of action of many of the complementary and alternative medicine (CAM) products are poorly defined, if at all. Here, we propose to study the immune system related mechanisms by which Celastrus, a TCM, suppresses arthritis in an experimental rat model that resembles human RA. The results of our study would help develop better therapeutic approaches for arthritis.